Drug releasing coatings for medical devices

ABSTRACT

Balloon catheters, methods for preparing balloon catheters, and uses of balloon catheters are disclosed. The balloon catheter includes an elongate member, an expandable balloon, and a coating layer overlying an exterior surface of the expandable balloon. The coating layer includes a total drug load of a hydrophobic therapeutic agent and a combination of additives including a first additive and a second additive. The hydrophobic therapeutic agent is paclitaxel, rapamycin, or paclitaxel and rapamycin. The first additive is a surfactant. The second additive is a chemical compound having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester groups.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/674,144, filed Aug. 10, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/067,739, filed Mar. 11, 2016, which is acontinuation of U.S. patent application Ser. No. 14/683,612, filed Apr.10, 2015, which is a continuation of U.S. patent application Ser. No.13/846,143, filed Mar. 18, 2013, which is a continuation of U.S. patentapplication Ser. No. 12/731,835, filed Mar. 25, 2010, which is acontinuation-in-part of U.S. patent application Ser. No. 12/121,986,filed May 16, 2008, which is a continuation-in-part of U.S. patentapplication Ser. No. 11/942,452, filed Nov. 19, 2007, which claimspriority to U.S. Provisional Application No. 60/981,380, filed Oct. 19,2007, U.S. Provisional Application No. 60/981,384, filed Oct. 19, 2007,U.S. Provisional Application No. 60/926,850, filed Apr. 30, 2007, U.S.Provisional Application No. 60/904,473, filed Mar. 2, 2007, U.S.Provisional Application No. 60/903,529, filed Feb. 26, 2007, U.S.Provisional Application No. 60/897,427, filed Jan. 25, 2007, U.S.Provisional Application No. 60/880,742, filed Jan. 17, 2007, and U.S.Provisional Application No. 60/860,084, filed Nov. 20, 2006. The fulldisclosures of all of the foregoing applications are incorporated byreference herein.

TECHNICAL FIELD

The present disclosure relates to balloon catheters, methods ofpreparing balloon catheters, and uses of balloon catheters. Morespecifically, the present disclosure relates to balloon catheters fordelivering a therapeutic agent to a blood vessel, wherein the ballooncatheters have a coating layer having a hydrophobic therapeutic agentand a combination of additives.

BACKGROUND

It has become increasingly common to treat a variety of medicalconditions by introducing a medical device into the vascular system orother lumen within a human. While such treatment initially appearssuccessful, the initial success is often compromised by the recurrenceof disease, such as stenosis (i.e., restenosis) after such treatment.Restenosis involves a physiological response to vascular injury causedby angioplasty. Over time, de-endothelization and injury to smoothmuscle cells results in thrombus deposition, leukocyte and macrophageinfiltration, smooth muscle cell proliferation/migration, fibrosis, andextracellular matrix deposition. In response to the incidence ofrestenosis, numerous local drug delivery systems have been developed forthe treatment restenosis after balloon angioplasty.

Balloon catheters are one such local delivery system that has been foundto be effective in the treatment and prevention of restenosis.Generally, balloons coated with an active agent are pressed against thewall of a blood vessel when the blood vessel is dilated to deliver theactive agent. Accordingly, it may be advantageous for the active agentin the coating to be rapidly released and absorbed by blood vesseltissues. Any component in the coating which inhibits rapid release ofthe active agent may be disadvantageous.

The iodine contrast agent iopromide has been used with paclitaxel tocoat balloon catheters and has met some success in the treatment ofrestenosis. While it has been reported that such contrast agent improvesadhesion of paclitaxel to the balloon surface, iodinated contrast agentssuffer from a variety of disadvantages. For example, when used fordiagnostic procedures, iodinated contrast agents have complication ratesof 5-30%. Additionally, iodinated contrast agents are associated withthe risk of bradycardia, ventricular arrthymia, and fibrillation, andmay also induce renal failure. Further, the Food and Drug Administrationissued a second public health advisory in 2006 concerning a serious lateadverse reaction to contrast agents known as Nephrogenic SystemicFibrosis or Mephrogenic Fibrosing Dermopathy.

Moreover, iodinated X-ray contrast agents are unable to cross membranelipid bilayers in order to enter cells of the vasculature. As a result,they are not optimally effective at carrying hydrophobic therapeuticagents such as paclitaxel into cells. The percentage of paclitaxelreported to be taken up by vascular tissue after deployment of thesedevices is only 5-20%. Additionally, the compatibility and/ormiscibility of paclitaxel and iopromide is not optimal, and theintegrity and uniformity of coating is poor. Such deficiencies adverselyaffect the amount and uniformity of hydrophobic therapeutic agentdelivered to target tissue. Accordingly, additional embodiments ofcoating layers for balloon catheters are desired.

SUMMARY

In one embodiment, a balloon catheter for delivering a therapeutic agentto a blood vessel is disclosed. The balloon catheter delivers atherapeutic agent to the blood vessel while the balloon catheter isdeployed at a target site of the blood vessel. The balloon catheterincludes an elongate member, an expandable balloon, and a coating layer.The elongate member has a lumen and a distal end. The expandable balloonis attached to the distal end of the elongate member and is in fluidcommunication with the lumen of the elongate member. The coating layeroverlies an exterior surface of the expandable balloon. The coatinglayer includes a total drug load of a hydrophobic therapeutic agent anda combination of additives including a first additive and a secondadditive. The hydrophobic therapeutic agent is one of paclitaxel,rapamycin, or combinations thereof. The first additive is one of PEGsorbitan monolaurates, PEG sorbitan monooleates, or combinationsthereof. The second additive is one of sorbitol, sorbitan, xylitol,gluconolactone, lactobionic acid, or combinations thereof.

In another embodiment, a balloon catheter for delivering a therapeuticagent to a blood vessel is disclosed. The balloon catheter delivers atherapeutic agent to the blood vessel while the balloon catheter isdeployed at a target site of the blood vessel. In this embodiment, theballoon catheter includes an elongate member, an expandable balloon, anda coating layer. The elongate member has a lumen and a distal end. Theexpandable balloon is attached to the distal end of the elongate memberand is in fluid communication with the lumen of the elongate member. Thecoating layer overlies an exterior surface of the expandable balloon. Inthis embodiment, the coating layer includes a total drug load of ahydrophobic therapeutic agent and a combination of additives including afirst additive and a second additive. The total drug load of thehydrophobic therapeutic agent is from 2.5 μg to 6 μg per squaremillimeter of the expandable balloon. The hydrophobic therapeutic agentis one of paclitaxel, rapamycin, or combinations thereof. The firstadditive is one of PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonooleate, or combinations thereof. The second additive is one ofsorbitol, gluconolactone, or combinations thereof. The ratio by weightof the combination of additives in the coating layer to the hydrophobictherapeutic agent in the coating layer is about 10 to 0.5.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present disclosure as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present disclosure;

FIG. 2A is a cross-sectional view of an embodiment of the distal portionof the balloon catheter of FIG. 1, taken along line A-A, showing anexemplary coating layer;

FIG. 2B is a cross-sectional view of an embodiment of the distal portionof the balloon catheter of FIG. 1, taken along line A-A, showing anexemplary coating layer; and

FIG. 2C is a cross-sectional view of an embodiment of the distal portionof the balloon catheter of FIG. 1, taken along line A-A, showing anexemplary coating layer.

Skilled artisans should appreciate that elements in the figures areillustrated for simplicity and clarity and are not necessarily drawn toscale. For example, the dimensions of some of the elements in thefigures may be exaggerated relative to other elements, as well asconventional parts removed, to help to improve understanding of thevarious embodiments described herein.

DETAILED DESCRIPTION

Embodiments of the present disclosure relate to balloon catheters fordelivering a therapeutic agent to a blood vessel. In one embodiment, theballoon catheter includes an elongate member, an expandable balloon, anda coating layer. Reference will now be made in detail to ballooncatheters. More particularly, embodiments of the balloon catheter and,more specifically, the elongate member and the expandable balloon of theballoon catheter will now be described in detail with reference toFIG. 1. Thereafter, embodiments of the coating layer will be describedin detail with reference to FIG. 2.

I. Balloon Catheters with Coating Layer

Referring to FIG. 1, a balloon catheter 10 is disclosed. The ballooncatheter 10 has a proximal end 18 and a distal end 20. The ballooncatheter 10 may be any suitable catheter for desired use, includingconventional balloon catheters known to one of ordinary skill in theart. For example, the balloon catheter 10 may be a rapid exchange orover-the-wire catheter. The balloon catheter 10 may be made of anysuitable biocompatible material.

As shown in FIGS. 1 and 2, in one embodiment, the balloon catheter 10includes an expandable balloon 12 and an elongate member 14. Theelongate member 14 extends between the proximal end 18 and the distalend 20 of the balloon catheter 10. The elongate member 14 has at leastone lumen 26 a, 26 b and a distal end 22. The elongate member 14 may bea flexible member which is a tube made of suitable biocompatiblematerial. The elongate member 14 may have one lumen or, as shown inFIGS. 1 and 2, more than one lumen 26 a, 26 b therein. For example, theelongate member 14 may include a guide-wire lumen 26 b that extends tothe distal end 20 of the balloon catheter 10 from a guide-wire port 15at the proximal end 18 of the balloon catheter 10. The elongate member14 may also include an inflation lumen 26 a that extends from aninflation port 17 of the balloon catheter 10 to the inside of theexpandable balloon 12 to enable inflation of the expandable balloon 12.From the embodiment of FIGS. 1 and 2, even though the inflation lumen 26a and the guide-wire lumen 26 b are shown as side-by-side lumens, itshould be understood that the one or more lumens present in the elongatemember 14 may be configured in any manner suited to the intendedpurposes of the lumens including, for example, introducing inflationmedia and/or introducing a guide-wire. Many such configurations are wellknown in the art.

The expandable balloon 12 is attached to the distal end 22 of theelongate member 14. The expandable balloon 12 has an exterior surface 24and is inflatable. The expandable balloon 12 is in fluidic communicationwith a lumen of the elongate member 14, (for example, with the inflationlumen 26 a). At least one lumen of the elongate member 14 is configuredto receive inflation media and to pass such media to the expandableballoon 12 for its expansion. Examples of inflation media include air,saline, and contrast media.

Still referring to FIG. 1, in one embodiment, the balloon catheter 10includes a handle assembly such as a hub 16. The hub 16 may be attachedto the balloon catheter 10 at the proximal end 18 of the ballooncatheter 10. The hub 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media or a guidewire. For example, a source of inflation media (not shown) may connectto the inflation port 17 of the hub 16 (for example, through theinflation lumen 26 a), and a guide wire (not shown) may be introduced tothe guide-wire port 15 of the hub 16, (for example through theguide-wire lumen 26 b).

Referring now to FIG. 2, a balloon catheter 10 having a coating layer 30is disclosed. The coating layer 30 overlies an exterior surface 24 ofthe expandable balloon 12. The coating layer 30 includes a hydrophobictherapeutic agent and a combination of additives. In one particularembodiment, the coating layer 30 consists essentially of the hydrophobictherapeutic agent and the combination of additives. Stated another way,in this particular embodiment, the coating layer 30 includes only thetherapeutic agent and the combination of additives, without any othermaterially significant components. In another particular embodiment, thecoating layer 30 is from about 0.1 μm to 15 μm thick.

A. Hydrophobic Therapeutic Agent

In one embodiment, the coating layer 30 includes a hydrophobictherapeutic agent. However, the coating layer 30 may also include two ormore hydrophobic therapeutic agents. The hydrophobic therapeutic agentmay be a lipophilic substantially water insoluble therapeutic agent. Forexample, the hydrophobic therapeutic agent may be paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and analogues andderivative thereof, and vitamin D3 and analogues and derivativesthereof. Additional suitable hydrophobic therapeutic agents generallyinclude glucocorticoids (e.g., dexamethasone, betamethasone), hirudin,angiopeptin, aspirin, growth factors, antisense agents, polynucleotides,RNAi, siRNA, anti-cancer agents, anti-proliferative agents,oligonucleotides, and, more generally, anti-platelet agents,anti-coagulant agents, anti-mitotic agents, anti-metabolite agents,antioxidants, antibiotic agents, anti-chemotactic, anti-inflammatoryagents, photosensitizing agents, and collagen synthesis inhibitors.

With regard to antisense agents, polynucleotides, RNAi, and siRNA,suitable hydrophobic therapeutic agents include agents that inhibitinflammation and/or smooth muscle cell or fibroblast proliferation. Withregard to anti-proliferative agents, suitable hydrophobic therapeuticagents include amlodipine and doxazocin. With regard to anti-plateletagents, suitable hydrophobic therapeutic agents include aspirin anddipyridamole. Aspirin may also be classified as an anti-platelet and ananti-inflammatory agent. Additionally, dipyridamole also exhibitsanti-platelet characteristics. With regard to anti-coagulant agents,suitable hydrophobic therapeutic agents include heparin, protamine,hirudin, and tick anticoagulant protein.

With regard to anti-mitotic agents and anti-metabolite agents, suitablehydrophobic therapeutic agents include methotrexate, azathioprine,vincristine, vinblastine, 5-fluorouracil, adriamycin, and mutamycin.With regard to antioxidants, suitable hydrophobic therapeutic agentsinclude probucol. With regard to antibiotic agents, suitable hydrophobictherapeutic agents include penicillin, cefoxitin, oxacillin, tobramycin,and gentamicin. With regard to photosensitizing agents, suitablehydrophobic therapeutic agents include agents for photodynamic orradiation therapy, including various porphyrin compounds such asporfimer. With regard to collagen synthesis inhibitors, suitablehydrophobic therapeutic agents include tranilast.

In one embodiment, the hydrophobic therapeutic agent includes at leastone of paclitaxel or analogs thereof, rapamycin or analogs thereof,beta-lapachone or analogues thereof, biological vitamin D or analogsthereof, and combinations thereof. In one particular embodiment, thehydrophobic therapeutic agent is paclitaxel, rapamycin, or combinationsthereof. In a further embodiment, the hydrophobic therapeutic agent ispaclitaxel. Alternatively, in another further embodiment, thehydrophobic therapeutic agent is rapamycin.

As used herein, “derivative” refers to a chemically or biologicallymodified version of a chemical compound that is structurally similar toa parent compound and (actually or theoretically) derivable from thatparent compound. A derivative may or may not have different chemical orphysical properties of the parent compound. For example, the derivativemay be more hydrophilic or it may have altered reactivity as compared tothe parent compound. Derivatization (i.e., modification) may involvesubstitution of one or more moieties within the molecule (e.g., a changein functional group). For example, a hydrogen may be substituted with ahalogen, such as fluorine or chlorine, or a hydroxyl group (—OH) may bereplaced with a carboxylic acid moiety (—COOH). The term “derivative”also includes conjugates, and prodrugs of a parent compound (i.e.,chemically modified derivatives which can be converted into the originalcompound under physiological conditions). For example, the prodrug maybe an inactive form of an active agent. Under physiological conditions,the prodrug may be converted into the active form of the compound.Prodrugs may be formed, for example, by replacing one or two hydrogenatoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamategroup (carbamate prodrugs). More detailed information relating toprodrugs is found, for example, in Fleisher et al., Advanced DrugDelivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.),Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991) 443. Theterm “derivative” is also used to describe all solvates, for examplehydrates or adducts (e.g., adducts with alcohols), active metabolites,and salts of the parent compound. The type of salt that may be prepareddepends on the nature of the moieties within the compound. For example,acidic groups, for example carboxylic acid groups, can form alkali metalsalts or alkaline earth metal salts (e.g., sodium salts, potassiumsalts, magnesium salts and calcium salts, as well as salts withphysiologically tolerable quaternary ammonium ions and acid additionsalts with ammonia and physiologically tolerable organic amines such astriethylamine, ethanolamine or tris-(2-hydroxyethyl)amine). Basic groupscan form acid addition salts, for example with inorganic acids such ashydrochloric acid, sulfuric acid or phosphoric acid, or with organiccarboxylic acids and sulfonic acids such as acetic acid, citric acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonicacid or p-toluenesulfonic acid. Compounds which simultaneously contain abasic group and an acidic group, for example a carboxyl group inaddition to basic nitrogen atoms, can be present as zwitterions. Saltscan be obtained by customary methods known to those skilled in the art,for example by combining a compound with an inorganic or organic acid orbase in a solvent or diluent, or from other salts by cation exchange oranion exchange.

As used herein, “analog” or “analogue” refers to a chemical compoundthat is structurally similar to another but differs slightly incomposition (as in the replacement of one atom by an atom of a differentelement or in the presence of a particular functional group), but may ormay not be derivable from the parent compound. A “derivative” differsfrom an “analog” or “analogue” in that a parent compound may be thestarting material to generate a “derivative,” whereas the parentcompound may not necessarily be used as the starting material togenerate an “analog.”

Numerous paclitaxel analogs are known in the art. Examples of paclitaxelinclude docetaxol (TAXOTERE, Merck Index entry 3458), and3′-desphenyl-3′-(4-nitrophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol.Further representative examples of paclitaxel analogs that can be usedas therapeutic agents include 7-deoxy-docetaxol, 7,8-cyclopropataxanes,N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modifiedpaclitaxels, 10-desacetoxytaxol, 10-deacetyltaxol (from10-deacetylbaccatin III), phosphonooxy and carbonate derivatives oftaxol, taxol 2′,7-di(sodium 1,2-benzenedicarboxylate,10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives,10-desacetoxytaxol, Protaxol (2′- and/or 7-O-ester derivatives), (2′-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxol sidechain, fluoro taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III,9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol),derivatives containing hydrogen or acetyl group and a hydroxy andtert-butoxycarbonylamino, sulfonated 2′-acryloyltaxol and sulfonated2′-O-acyl acid taxol derivatives, succinyltaxol, 2′-γ-aminobutyryltaxolformate, 2′-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol,2′-OH-7-PEG(5000) carbamate taxol, 2′-benzoyl and 2′,7-dibenzoyl taxolderivatives, other prodrugs (2′-acetyltaxol; 2′,7-diacetyltaxol;2′succinyltaxol; 2′-(beta-alanyl)-taxol); 2′gamma-aminobutyryltaxolformate; ethylene glycol derivatives of 2′-succinyltaxol;2′-glutaryltaxol; 2′-(N,N-dimethylglycyl)taxol;2′-(2-(N,N-dimethylamino)propionyl)taxol; 2′orthocarboxybenzoyl taxol;2′aliphatic carboxylic acid derivatives of taxol, Prodrugs{2′(N,N-diethylaminopropionyl)taxol, 2′(N,N-dimethylglycyl)taxol,7(N,N-dimethylglycyl)taxol, 2′,7-di-(N,N-dimethylglycyl)taxol,7(N,N-diethylaminopropionyl)taxol,2′,7-di(N,N-diethylaminopropionyl)taxol, 2′-(L-glycyl)taxol,7-(L-glycyl)taxol, 2′,7-di(L-glycyl)taxol, 2′-(L-alanyl)taxol,7-(L-alanyl)taxol, 2′,7-di(L-alanyl)taxol, 2′-(L-leucyl)taxol,7-(L-leucyl)taxol, 2′,7-di(L-leucyl)taxol, 2′-(L-isoleucyl)taxol,7-(L-isoleucyl)taxol, 2′,7-di(L-isoleucyl)taxol, 2′-(L-valyl)taxol,7-(L-valyl)taxol, 2′7-di(L-valyl)taxol, 2′-(L-phenylalanyl)taxol,7-(L-phenylalanyl)taxol, 2′,7-di(L-phenylalanyl)taxol,2′-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2′,7-di(L-prolyl)taxol,2′-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2′,7-di(L-lysyl)taxol,2′-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2′,7-di(L-glutamyl)taxol,2′-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2′,7-di(L-arginyl)taxol, taxolanalogues with modified phenylisoserine side chains, TAXOTERE,(N-debenzoyl-N-tert-(butoxycarbonyl)-10-deacetyltaxol, and taxanes(e.g., baccatin III, cephalomannine, 10-deacetylbaccatin III,brevifoliol, yunantaxusin and taxusin); and other taxane analogues andderivatives, including 14-beta-hydroxy-10 deacetybaccatin III,debenzoyl-2-acyl paclitaxel derivatives, benzoate paclitaxelderivatives, phosphonooxy and carbonate paclitaxel derivatives,sulfonated 2′-acryloyltaxol; sulfonated 2′-O-acyl acid paclitaxelderivatives, 18-site-substituted paclitaxel derivatives, chlorinatedpaclitaxel analogues, C4 methoxy ether paclitaxel derivatives,sulfenamide taxane derivatives, brominated paclitaxel analogues, Girardtaxane derivatives, nitrophenyl paclitaxel, 10-deacetylated substitutedpaclitaxel derivatives, 14-beta-hydroxy-10 deacetylbaccatin III taxanederivatives, C7 taxane derivatives, C10 taxane derivatives,2-debenzoyl-2-acyl taxane derivatives, 2-debenzoyl and -2-acylpaclitaxel derivatives, taxane and baccatin III analogues bearing new C2and C4 functional groups, n-acyl paclitaxel analogues,10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin IIIderivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl-4-acylpaclitaxel analogues, orthro-ester paclitaxel analogues, 2-aroyl-4-acylpaclitaxel analogues and 1-deoxy paclitaxel and 1-deoxy paclitaxelanalogues.

Other examples of paclitaxel analogs suitable for use herein includethose listed in U.S. Pat. App. Pub. No. 2007/0212394, and U.S. Pat. No.5,440,056, each of which is incorporated herein by reference.

Many rapamycin analogs are known in the art. Non-limiting examples ofanalogs of rapamycin include, but are not limited to, everolimus,tacrolimus, CCI-779, ABT-578, AP-23675, AP-23573, AP-23841,7-epi-rapamycin, 7-thiomethyl-rapamycin,7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin,prerapamycin, temsirolimus, and 42-O-(2-hydroxy)ethyl rapamycin.

Other analogs of rapamycin include: rapamycin oximes (U.S. Pat. No.5,446,048); rapamycin aminoesters (U.S. Pat. No. 5,130,307); rapamycindialdehydes (U.S. Pat. No. 6,680,330); rapamycin 29-enols (U.S. Pat. No.6,677,357); O-alkylated rapamycin derivatives (U.S. Pat. No. 6,440,990);water soluble rapamycin esters (U.S. Pat. No. 5,955,457); alkylatedrapamycin derivatives (U.S. Pat. No. 5,922,730); rapamycin amidinocarbamates (U.S. Pat. No. 5,637,590); biotin esters of rapamycin (U.S.Pat. No. 5,504,091); carbamates of rapamycin (U.S. Pat. No. 5,567,709);rapamycin hydroxyesters (U.S. Pat. No. 5,362,718); rapamycin42-sulfonates and 42-(N-carbalkoxy)sulfamates (U.S. Pat. No. 5,346,893);rapamycin oxepane isomers (U.S. Pat. No. 5,344,833); imidazolidylrapamycin derivatives (U.S. Pat. No. 5,310,903); rapamycin alkoxyesters(U.S. Pat. No. 5,233,036); rapamycin pyrazoles (U.S. Pat. No.5,164,399); acyl derivatives of rapamycin (U.S. Pat. No. 4,316,885);reduction products of rapamycin (U.S. Pat. Nos. 5,102,876 and5,138,051); rapamycin amide esters (U.S. Pat. No. 5,118,677); rapamycinfluorinated esters (U.S. Pat. No. 5,100,883); rapamycin acetals (U.S.Pat. No. 5,151,413); oxorapamycins (U.S. Pat. No. 6,399,625); andrapamycin silyl ethers (U.S. Pat. No. 5,120,842), each of which isspecifically incorporated by reference.

Other analogs of rapamycin include those described in U.S. Pat. Nos.7,560,457; 7,538,119; 7,476,678; 7,470,682; 7,455,853; 7,446,111;7,445,916; 7,282,505; 7,279,562; 7,273,874; 7,268,144; 7,241,771;7,220,755; 7,160,867; 6,329,386; RE37,421; 6,200,985; 6,015,809;6,004,973; 5,985,890; 5,955,457; 5,922,730; 5,912,253; 5,780,462;5,665,772; 5,637,590; 5,567,709; 5,563,145; 5,559,122; 5,559,120;5,559,119; 5,559,112; 5,550,133; 5,541,192; 5,541,191; 5,532,355;5,530,121; 5,530,007; 5,525,610; 5,521,194; 5,519,031; 5,516,780;5,508,399; 5,508,290; 5,508,286; 5,508,285; 5,504,291; 5,504,204;5,491,231; 5,489,680; 5,489,595; 5,488,054; 5,486,524; 5,486,523;5,486,522; 5,484,791; 5,484,790; 5,480,989; 5,480,988; 5,463,048;5,446,048; 5,434,260; 5,411,967; 5,391,730; 5,389,639; 5,385,910;5,385,909; 5,385,908; 5,378,836; 5,378,696; 5,373,014; 5,362,718;5,358,944; 5,346,893; 5,344,833; 5,302,584; 5,262,424; 5,262,423;5,260,300; 5,260,299; 5,233,036; 5,221,740; 5,221,670; 5,202,332;5,194,447; 5,177,203; 5,169,851; 5,164,399; 5,162,333; 5,151,413;5,138,051; 5,130,307; 5,120,842; 5,120,727; 5,120,726; 5,120,725;5,118,678; 5,118,677; 5,100,883; 5,023,264; 5,023,263; 5,023,262; all ofwhich are incorporated herein by reference. Additional rapamycin analogsand derivatives can be found in the following U.S. Patent ApplicationPub. Nos., all of which are herein specifically incorporated byreference: 20080249123, 20080188511; 20080182867; 20080091008;20080085880; 20080069797; 20070280992; 20070225313; 20070203172;20070203171; 20070203170; 20070203169; 20070203168; 20070142423;20060264453; and 20040010002.

In another embodiment, the hydrophobic therapeutic agent is provided asa total drug load in the coating layer 20. The total drug load of thehydrophobic therapeutic agent in the coating layer 30 may be from 1 μgto 20 μg, or alternatively from 2 μg to 10 μg, or alternatively from 2μg to 6 μg, or alternatively from 2.5 μg to 6 μg per square millimeterof the expandable balloon 12. The hydrophobic therapeutic agent may alsobe uniformly distributed in the coating layer. Additionally, thehydrophobic therapeutic agent may be provided in a variety of physicalstates. For example, the hydrophobic therapeutic agent may be amolecular distribution, crystal form, or cluster form.

B. Combination of Additives

The coating layer 30 also includes a combination of additives. Thecombination of additives includes a first additive and a secondadditive. In one embodiment, the first additive is a surfactant and thesecond additive is a chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide, or ester groups.

1. First Additive

In one embodiment, the first additive is a surfactant. However, thefirst additive may also include mixtures of surfactants. Suchsurfactants may be anionic, cationic, zwitterionic, or non-ionic.Examples of suitable non-ionic surfactants include polyethylene glycolfatty acids, polyethylene glycol fatty acid mono and diesters,polyethylene glycol glycerol fatty acid esters, alcohol-oiltransesterification products, polyglyceryl fatty acids, propylene glycolfatty acid esters, sterol and sterol derivatives, polyethylene glycolsorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar andderivatives thereof, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, and sorbitan fattyacid esters. Examples of suitable ionic surfactants include quaternaryammonium salts, fatty acid salts, and bile salts.

With regard to polyethylene glycol (hereinafter “PEG”) fatty acids,suitable hydrophilic surfactants include monoesters, esters of lauricacid, oleic acid, and stearic acid. Examples of such surfactants includePEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate,PEG-20 laurate, and PEG-20 oleate. With regard to PEG fatty aciddiesters, suitable hydrophilic surfactants include PEG-20 dilaurate,PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, and PEG-32dioleate. With regard to PEG fatty acids, suitable hydrophilicsurfactants include PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryloleate.

With regard to alcohol-oil transesterification products, suitablesurfactants can be prepared by reaction of alcohol or polyalcohol with avariety of natural and/or hydrogenated oils. Examples of such alcoholsinclude glycerol, propylene glycol, ethylene glycol, PEG, sorbitol, andpentaerythritol. Examples of such oils include castor oil, hydrogenatedcastor oil, corn oil, olive oil, peanut oil, palm kernel oil, apricotkernel oil, or almond oil. Examples of hydrophilic surfactants preparedby such reaction include PEG-35 castor oil, PEG-40 hydrogenated castoroil, PEG-25 trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40palm kernel oil, PEG-50 castor oil, PEG-50 hydrogenated castor oil,PEG-8 caprylic/capric glycerides, and PEG-6 caprylic/capric glycerides.Examples of hydrophobic surfactants prepared by such reaction includePEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricotkernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palmkernel oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil,PEG-20 corn glycerides, and PEG-20 almond glycerides.

With regard to polyglyceryl fatty acids, suitable hydrophobicsurfactants include polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl oleate, polyglyceryl-2 diolate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Suitable hydrophilic surfactants include polyglyceryl-10laurate, polyglyceryl-10 oleate, and polyglyceryl-10 mono, diolate,polyglyceryl-10 stearate, polyglyceryl-10 linoleate, polyglyceryl-6stearate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (i.e. polymuls) are also suitablesurfactants.

With regard to propylene glycol fatty acid esters, suitable hydrophobicsurfactants include propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, and propylene glycol dioctanoate. With regard tosterol and sterol derivatives, suitable surfactants include PEGderivatives such as PEG-24 cholesterol ether.

With regard to PEG sorbitan fatty acid esters, suitable surfactantsinclude PEG sorbitan monolaurates, PEG sorbitan monopalmitates, PEGsorbitan monooleates, and PEG sorbitan monostearates. Examples of suchsurfactants include PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monooleate, and PEG-20 sorbitanmonostearate. With regard to PEG alkyl ethers, suitable surfactantsinclude PEG-3 oleyl ether and PEG-4 lauryl-ether.

With regard to sugars and derivatives thereof, suitable surfactantsinclude sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, and octyl-β-D-thioglucopyranoside. Withregard to PEG alkyl phenols, suitable surfactants include PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, tyloxapol, octoxynol, andnonoxynol.

With regard to polyoxyethylene-polyoxypropylene (hereinafter “POE-POP”)block copolymers, such block copolymers include hydrophilicpolyoxyethylene and hydrophobic polyoxypropylene moieties having theformula HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denotethe number of polyoxyethylene and polyoxypropylene units, respectively.Such polymers are referred to as poloxamers. Suitable hydrophilicpoloxamers include Poloxamers 108, 188, 217, 238, 288, 338, and 407.Suitable hydrophobic poloxamers include Poloxamers 124, 182, 183, 212,313, and 335. With regard to sorbitan fatty acid esters, suitablehydrophobic surfactants include sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monooleate, and sorbitan monostearate.

With regard to ionic surfactants, suitable ionic surfactants includebenzalkonium chloride, benzethonium chloride, cetylpyridinium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, edrophonium chloride, domiphen bromide,dialkylesters of sodium sulfonsuccinic acid, sodium dioctylsulfosuccinate, sodium cholate, and sodium taurocholate.

Such surfactants are stable under heating and are capable of survivingan ethylene oxide sterilization process (which may be employed inpreparing the balloon catheters). Moreover, such surfactants do notreact with paclitaxel or rapamycin under the sterilization process.Additionally, such surfactants may protect the hydrophobic therapeuticagents from premature release during the device delivery process whilefacilitating rapid release and elution of the hydrophobic therapeuticagent.

In one embodiment, the surfactant is a PEG sorbitan monolaurate, a PEGsorbitan monooleate, or a combination thereof. In one particularembodiment, the surfactant is a PEG sorbitan monolaurate, and in afurther embodiment, the surfactant is PEG-20 sorbitan monolaurate (i.e.Tween-20). In another particular embodiment, the surfactant is a PEGsorbitan monooleate, and in a further embodiment, the surfactant isPEG-20 sorbitan monooleate (i.e. Tween-80).

2. Second Additive

In one embodiment, the second additive is a chemical compound having oneor more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estergroups. However, the second additive may also include mixtures ofchemical compounds having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups. The chemical compound has atleast one hydroxyl group. The hydroxyl group is suitable as thehydrophilic moiety because it is unlikely to react with the hydrophobictherapeutic agent. In one particular embodiment, the chemical compoundhas a molecular weight less than 5,000-10,000, or alternatively lessthan 750-1,000, or alternatively less than 750. In a further embodiment,the chemical compound has a molecular weight of greater than 80. In anexemplary embodiment, the chemical compound has a molecular weight lessthan that of the hydrophobic therapeutic agent.

In one embodiment, the chemical compound has four or more hydroxylgroups. In one particular embodiment, the chemical compound having morethan four hydroxyl groups has a melting point of 120° C. or less. Inanother particular embodiment, the chemical compound has three adjacenthydroxyl groups that in stereo configuration are all on one side of themolecule. Without being bound by the theory, it is believed that thestereo configuration of the three adjacent hydroxyl groups may enhancedrug binding.

Large molecules diffuse slowly. If the molecular weight of the additiveor the chemical compound is high, for example above 800, above 1000,above 1200, above 1500, or above 2000, the chemical compound may eluteoff of the exterior surface 24 of the expandable balloon 12 too slowly.For example, the hydrophobic therapeutic agent may be released ingreater than two minutes. However, if the chemical compound has morethan four hydroxyl groups it will have increased hydrophilic propertiessuch that the hydrophobic therapeutic agent may elute off of theexterior surface 24 of the expandable balloon 12 quickly. For example,the hydrophobic therapeutic agent may be released at the target site inless than two minutes. Without being bound by the theory, it is believedthat the increased hydrophilicity may play a role in: (1) aiding in theelution of the coating layer 30 off of the exterior surface 24 of theexpandable balloon 12; (2) accelerating the release of the hydrophobictherapeutic agent; and (3) improving or facilitating the movement of thehydrophobic therapeutic agent through the water barriers and the polarhead groups of lipid bilayers in cells membranes to penetrate tissues.

Examples of chemical compounds having one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide, or ester moieties include aminoalcohols, hydroxyl carboxylic acids, esters, and anhydrides, hydroxylketones, hydroxyl lactones, hydroxyl esters, sugar phosphates, sugarsulfate ethyl oxides, ethyl glycols, amino acids and salts thereof,peptides, proteins, sorbitan, glycerol, polyalcohols, phosphates,sulfates, organic acids, esters, salts, vitamins, and combinations ofamino alcohols and organic acids.

With regard to amino acids and salts thereof, suitable chemicalcompounds include alanine, arginine, asparagines, aspartic acid,cysteine, cystine, glutamic acid, glutamine, glycine, histidine,proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine,threonine, tryptophan, tyrosine, valine, and derivatives thereof.Additionally, amino acid dimers, sugar conjugates, and derivativesthereof may also be suitable chemical compounds. For example,catecholamines such as dopamine, levodopa, carbidoga, and DOPA may alsobe suitable chemical compounds.

With regard to peptides, oligopeptides and peptides are suitable aschemical compounds because hydrophobic and hydrophilic amino acids maybe coupled to create various sequences of amino acids, facilitatingpermeation of tissue by the hydrophobic therapeutic agent. With regardto proteins, suitable chemical compounds include albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, and lipases.In an exemplary embodiment, the chemical compound is serum albumin. Suchprotein is suitable because it is water soluble and contains significanthydrophobic portions to bind the hydrophobic therapeutic agent.

With regard to vitamins, suitable chemical compounds include fat-solublevitamins and salts thereof and water-soluble vitamins and amphiphilicderivatives thereof. Suitable examples of fat-soluble vitamins and saltsthereof include alpha-tocopherol, beta-tocopherol, gamma-tocopherol,delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, vitaminK-S(II), and folic acid in free acid form. Suitable examples ofwater-soluble vitamins and amphiphilic derivatives thereof includeacetiamine, benfotiamine, pantothenic acid, cetotiamine, cyclothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU.

With regard to organic acids, esters, and anhydrides, suitable chemicalcompounds include acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid,aspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

With regard to amino alcohols, alcohols, amines, acids, amides, andhydroxyl acids, suitable chemical compounds include L-ascorbic acid andsalts thereof, D-glucoascorbic acid and salts thereof, tromethamine,triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone, lactobionic acid,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate,sugar sulphates, sinapic acid, vanillic acid, vanillin, methyl paraben,propyl paraben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose,ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose,fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and amine described above, polyglycidol,glycerols, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of PEG and polypropylene glycol,derivatives thereof, and combinations thereof.

Such chemical compounds are stable under heating and are capable ofsurviving an ethylene oxide sterilization process. Moreover, suchchemical compounds do not react with paclitaxel or rapamycin under thesterilization process. In particular, without being bound by the theory,it is believed that hydroxyl, ester, and amide groups are unlikely toreact with hydrophobic therapeutic agents such as paclitaxel orrapamycin. However, with specific regard to L-ascorbic acid and saltsthereof as well as diethanolamine, such chemical compounds do notnecessarily survive such sterilization processes and do react withpaclitaxel. Additionally, in some instances, amine and acid groups(e.g., benzoic acid, gentisic acid, diethanolamine, and ascorbic acid)do react with hydrophobic therapeutic agents such as paclitaxel and maynot be stable under ethylene oxide sterilization, heating, and agingprocesses. Accordingly, different sterilization methods should beemployed with regard to such specific chemical compounds. Finally, whilethe chemical compounds described herein rapidly elute the hydrophobictherapeutic agent off of the expandable balloon 12 during deployment atthe target site, absorption of the hydrophobic therapeutic agent bytissue is unexpectedly high. Such is particularly apparent with regardto hydroxyl lactones including ribonic acid lactone and gluconolactone.

In one embodiment, the chemical compound is sorbitol, sorbitan, xylitol,gluconolactone, lactobionic acid, or a combination thereof. In oneparticular embodiment, the chemical compound is sorbitol,gluconolactone, or combinations thereof. In a further embodiment, thechemical compound is sorbitol. Alternatively, in a further particularembodiment, the chemical compound is gluconolactone.

Additionally, the surfactants and combinations of surfactants describedherein may also be employed in combination with the chemical compoundsand combinations of chemical compounds described herein. For example, inone particular embodiment, the coating layer includes a hydrophobictherapeutic agent, a first additive, and a second additive, wherein thehydrophobic therapeutic agent is paclitaxel, the first additive isPEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, or combinationsthereof, and the second additive is one of sorbitol, gluconolactone, orcombinations thereof. In another particular embodiment, the coatinglayer includes a hydrophobic therapeutic agent, a first additive, and asecond additive, wherein the hydrophobic therapeutic agent ispaclitaxel, the first additive is PEG-20 sorbitan monolaurate, and thesecond additive is sorbitol. In yet another particular embodiment, thecoating layer includes a hydrophobic therapeutic agent, a firstadditive, and a second additive, wherein the hydrophobic therapeuticagent is paclitaxel, and the second additive is gluconolactone.

In one embodiment, the combination of additives in the coating layer 30is from 1 μg to 20 μg. In another embodiment, the combination ofadditives and the hydrophobic therapeutic agent are provided in specificweight ratios in the coating layer 30. For example, the ratio by weightof the combination of additives in the coating layer 30 to thehydrophobic therapeutic agent in the coating layer 30 is about 20 to0.05, or alternatively about 10 to 0.5, or alternatively about 5 to 0.8.Alternatively, in another embodiment, the ratio by weight of thehydrophobic therapeutic agent in the coating layer 30 to the combinationof additives is about 0.5 to 3. In yet another embodiment, the ballooncatheter 10 is capable of releasing the hydrophobic therapeutic agentand the combination of additives to the tissue in about 0.1 to 30minutes, or alternatively in about 0.1 to 10 minutes, or alternativelyin about 0.2 to 2 minutes, or alternatively in about 0.1 to 1 minute.Such timing of release refers to the timing during which the expandableballoon 12 is inflated and pressing the coating layer 30 into contactwith the target tissue.

C. Solvents

The hydrophobic therapeutic agent is water insoluble. The combination ofadditives is soluble in aqueous solvent and polar organic solvent. Suchaqueous solvent and polar organic solvents may be employed in preparingthe coating layer. Suitable aqueous solvents include water. Suitablepolar organic solvents include alkanes, aromatic solvents, alcohols,ethers, esters/acetates, ketones, and mixtures thereof.

With regard to alkanes, suitable solvents include hexane, octane,cyclohexane, and heptane. With regard to aromatic solvents, suitablesolvents include benzene, toluene, and xylene. With regard to alcohols,suitable solvents include methanol, ethanol, propanol, and isopropanol,diethylamide, ethylene glycol monoethyl ether, trascutol, and benzylalcohol. With regard to ethers, suitable solvents include dioxane,dimethyl ether and tetrahydrofuran. With regard to esters/acetates,suitable solvents include ethyl acetate and isobutyl acetate. Withregard to ketones, suitable solvents include acetone, acetonitrile,diethyl ketone, and methyl ethyl ketone. Suitable solvents also includemixtures of aqueous solvents and polar organic solvents. For example,suitable mixtures of aqueous solvents and polar organic solvents mayinclude water and ethanol, water and acetone, and water and methanol,water and tetrahydrofuran.

Embodiments of the balloon catheter have been described in detail.Further embodiments directed to methods of preparing balloon catheterswill now be described.

II. Methods for Preparing Balloon Catheters

Methods for preparing a balloon catheter 10 may include (1) preparing acoating solution including a solvent, a therapeutic agent, and acombination of additives, (2) loading a metering dispenser with thecoating solution, (3) inflating the balloon catheter 10 to 0 to 3 atm,and rotating the balloon catheter 10 about the longitudinal axis of thecatheter and/or moving the balloon catheter 10 in a linear directionalong the longitudinal or transverse axis of the balloon catheter 10,(4) dispensing the coating solution from the metering dispenser onto anexterior surface 24 of the balloon catheter 10 and flowing the coatingsolution on the surface of the balloon catheter 10 while the ballooncatheter 10 is rotating and/or linearly moving, (5) evaporating thesolvent, forming a coating layer 30 on the balloon catheter 10, (6)drying, folding, and wrapping the balloon catheter 10, and (7)sterilizing the balloon catheter 10. In one embodiment, the method forpreparing the balloon catheter 10 further includes (8) drying theballoon catheter 10 after sterilization.

The coating solution includes a solvent, a hydrophobic therapeuticagent, and a combination of additives. In one particular embodiment, thecoating solution consists essentially of the solvent, the hydrophobictherapeutic agent, and the combination of additives. The solvent, thehydrophobic therapeutic agent, and the combination of additives are aspreviously discussed. The content of the hydrophobic therapeutic agentin the coating solution can be from 0.5-50% by weight based on the totalweight of the solution. The content of the combination of additives inthe coating solution can be from 1-45% by weight, from 1 to 40% byweight, or from 1-15% by weight based on the total weight of thesolution. The amount of solvent employed is dependent upon the coatingprocess and viscosity.

In one particular embodiment, loading the metering dispenser with thecoating solution, inflating the balloon catheter 10 to 0 atm to 3 atm,dispensing the coating solution from the metering dispenser, andevaporating the solvent, (as set forth in (2)-(5) above), occurconcomitantly. In another embodiment, loading the metering dispenserwith the coating solution, inflating the balloon catheter 10 to 0 atm to3 atm, dispensing the coating solution from the metering dispenser, andevaporating the solvent, (as set forth in (2)-(5) above) are repeateduntil a therapeutically effective amount of the hydrophobic therapeuticagent in the coating solution is deposited on the exterior surface 24 ofthe balloon catheter 10.

A. Preparing a Coating Solution

With regard to preparing the coating solution, suitable techniques forpreparing the coating solution include dispersing, dissolving,diffusing, or otherwise mixing the solvent, the hydrophobic therapeuticagent, and the combination of additives (as previously discussed). Inone embodiment, the coating solution is prepared by mixing the solvent,the hydrophobic therapeutic agent, and the combination of additivestogether simultaneously.

Alternatively, in another embodiment, the coating solution may beprepared by adding the hydrophobic therapeutic agent and the combinationof additives sequentially to the solvent. Such technique of sequentiallyadding components to the solvent may be based upon solubility of suchcomponents and/or other parameters known in the art. For example, thecoating solution may be prepared by first adding the hydrophobictherapeutic agent to the solvent and then adding the combination ofadditives. Alternatively, the combination of additives may be addedfirst to the solvent, after which the hydrophobic therapeutic agent maybe added. Adding the combination of additives first to the solvent maybe beneficial wherein a hydrophobic therapeutic does not sufficientlydissolve in a solvent (when added prior to the combination ofadditives). Without being bound by the theory, it is believed that thecombination of additives will increase the solubility of the hydrophobictherapeutic agent in the solvent. In some embodiments, preparation ofthe coating solution may also involve homogenization under high shearconditions and optionally under pressure. In some embodiments, thepreparation of the coating solution may also involve filtering thecoating solution. For example, in one particular embodiment, the coatingsolution is prepared by: (1) mixing a fixed amount of the hydrophobictherapeutic agent, the combination of additives, and the solvent, (2)stirring the resulting mixture at room temperature, for example, or withslight heating such as to less than 60° C. until a homogenous solutionis obtained, and (3) filtering the solution through a 0.45 μm filter.

Alternatively, in another embodiment, combinations of two or moresolvents may be used, for example, by combining two solvents prior toaddition of a hydrophobic therapeutic agent and a combination ofadditives. As another example, combinations of two or more solvents maybe used by adding a hydrophobic therapeutic agent to one solvent and acombination of additives to another solvent and then combining. As stillanother example, combinations of two or more solvents may be used byadding only one of the hydrophobic therapeutic agent or the combinationof additives to one solvent and then adding the second solvent and theremaining hydrophobic therapeutic agent or the combination of additives.

B. Loading a Metering Dispenser with the Coating Solution

With regard to loading a metering dispenser with the coating solution,suitable metering dispensers are as disclosed in U.S. Pub. No.2010/0055294, the disclosure of which is incorporated by reference inits entirety. In one embodiment, the metering dispenser is a portion ofan apparatus for coating a balloon catheter 10. The apparatus forcoating a balloon catheter 10 may be semi-manual or automated. Briefly,in one embodiment, such apparatus includes an apparatus capable ofrotating the balloon catheter 10 around its longitudinal axis and movingthe balloon catheter 10 back and forth in the direction of itslongitudinal or transverse axis, a controller coordinating the dispenserand the apparatus, and a coating solution storage container.

In one embodiment, the metering dispenser includes a dispensing tipconnected to the metering dispenser for easy coating application. Thedispensing tip may include a hub and a tip. In one particularembodiment, the hub is connected to the metering dispenser. The tip maybe used to apply coating on the balloon catheter 10 either by contact ornon-contact. The tip opening may have different shapes including, butnot limited to, circular, oval, square, and rectangular. Additionally,the tip may be straight or with an angle (135°, 45° or 90°) and may berigid or flexible. The tip may be tapered, non-tapered, Teflon-lined,Teflon-coated, and Teflon-lined and crimped or may be a brush. In oneembodiment, the dispensing tip is made of metals, metal alloys, and ametal with a polymer coating or lining. For example, in one embodiment,the dispensing tip is made of stainless steel, polyethylene,polypropylene, polyesters, polyamides, polyurethanes, PTFE, metal with aPTFE coating or lining.

In another embodiment, the dispensing tip has an opening and a flexibletail. The flexible tail may be threaded through the tip opening of thedispensing tip or may be attached to the side of the tip. Inembodiments, the flexible tail contacts the expandable balloon 12 to becoated. In some embodiments, the metering dispenser is a syringe, asyringe pump, a metering pipette, or an automatic metering system. Inanother embodiment, the automatic metering system includes a microlinear pump module, a dispensing controller module, a dispensing tip andother accessories from IVEK Corporation.

C. Inflating the Balloon Catheter

With regard to inflating the expandable balloon 12 of the ballooncatheter 10, in one embodiment, the expandable balloon 12 is inflatedfrom 0 atm to about 3 atm. Additionally, the balloon catheter 10 may berotated about the longitudinal axis thereof and/or moved in a lineardirection along the longitudinal or transverse axis thereof.

In one particular embodiment, the apparatus for coating the ballooncatheter 10 concurrently rotates the balloon catheter 10 around itslongitudinal axis at uniform rotational or tangential speed andtranslocates the balloon catheter 10 back and forth at uniform frequencyin a longitudinal direction. More particularly, in this particularembodiment, the apparatus for coating the balloon catheter 10 moves theballoon catheter 10 linearly back and forth along a rail with uniformfrequency while rotating the balloon catheter 10 at uniformrotational/tangential speed.

In an alternative embodiment, the metering dispenser moves linearly backand forth along a rail with uniform frequency while the apparatuscapable of rotating the balloon catheter 10 rotates the balloon catheter10 at uniform rotational/tangential speed.

D. Dispensing the Coating Solution from the Metering Dispenser onto anExterior Surface 24 of the Balloon Catheter 10

With regard to dispensing the coating solution from the meteringdispenser onto an exterior surface 24 of the balloon catheter 10, in oneembodiment, the coating solution is dispensed from the meteringdispenser while the balloon catheter 10 is rotating and/or linearlymoving. During dispensing, the coating solution flows continuously tothe exterior surface 24 of the balloon catheter 10 without formingdroplets. In one embodiment, the drops of the coating solution move backand forth longitudinally and transversely over the exterior surface 24of the balloon catheter 10 while the solvent evaporates, resulting inthe consistent and uniform deposition of coating solution over theexterior surface 24 of the balloon catheter 10 and resulting in auniform dry coating layer over the exterior surface 24 of the ballooncatheter 10. Without being bound by the theory, it is believed that therotational and traversal movements allow the flexible tail to break thesurface tension between the coating and the expandable balloon 12,forming a uniform coating on the exterior surface 24 of the ballooncatheter 10.

During dispensing, in one embodiment, the balloon catheter 10 and/or thedispensing tip of the metering dispenser move transversely androtationally. In one particular embodiment, the rotation speed is from0.1 to 10 revolutions per second, or alternatively from 0.5 to 5revolutions per second, or alternatively from 0.8 to 2 revolutions persecond. The linear or transverse speed is from 0.1 mm per second to 100mm per second, or alternatively from 1 mm per second to 75 mm persecond, or from 2 mm per second to 50 mm per second. The dispensing timeis from 2 seconds to 300 seconds, or alternatively from 5 seconds to 120second. The dispensing time is dependent upon the dispensing coatingvolume and diameters and lengths of the balloon catheter 10.

E. Evaporating the Solvent Forming a Coating Layer 30 on the BalloonCatheter 10

With regard to evaporating the solvent, in one embodiment, the solventis evaporated while the coating solution is moving at a uniform speed.Without being bound by the theory, it is believed that such techniqueforms a substantially uniform dry coating layer 30 on the exteriorsurface 24 of the balloon catheter 10. In one particular embodiment, theapparatus for coating the balloon catheter 10 includes a fan foraccelerating solvent evaporation.

F. Drying, Folding, and Wrapping the Balloon Catheter 10

With regard to drying, folding, and wrapping the balloon catheter 10,the coating solution may solidify on the exterior surface 24 of theballoon catheter 10 during the transverse and rotational motion of theballoon catheter 10. In one embodiment, the time of solidifying of thecoating layer 30 on the expandable balloon 12 after dispensing of theliquid coating is from 0.1 minutes to 10 minutes, or alternatively from0.5 minutes to 5 minutes. Following solidification, in one embodiment,the coated balloon catheter 10 is dried at room temperature for 12 hoursto 24 hours.

The expandable balloon 12 may be folded after drying. Upon folding, thedried and folded balloon catheter 10 is rewrapped. Additionally, in oneparticular embodiment, a properly sized balloon protector is placed uponthe wrapped balloon catheter 10 and the balloon catheter 10 is packaged.

G. Sterilizing the Balloon Catheter 10

With regard to sterilizing the balloon catheter 10, suitablesterilization techniques may include, but should not be limited to,sterilization with ethylene oxide and sterilization with an electronbeam. In one particular embodiment, the balloon catheter 10 issterilized with ethylene oxide.

H. Drying the Balloon Catheter 10 after Sterilization

After sterilizing the balloon catheter 10, in one embodiment, theballoon catheter 10 is dried. More particularly, in one embodiment, theballoon catheter 10 is dried under vacuum at about 0° C. to 100° C. forapproximately 2 hours to 56 hours. In another embodiment, the ballooncatheter 10 is dried under vacuum at about 5° C. to about 45° C. Withoutbeing bound by the theory, it is believed that the drying processimproves integrity of the coating layer 30, protects loss of coatingcomponents during transit through body passages to the target treatmentsite, and improves drug absorption in the tissue.

I. Optional Post Treatment with DMSO

After depositing the coating layer 30 on the balloon catheter 10, in oneembodiment, DMSO or other solvent is applied to the surface of thecoating layer 20. The DMSO or other solvent may be applied to thesurface by dipping, spraying, or any other suitable method known in theart. DMSO readily dissolves hydrophobic therapeutic agents andpenetrates the membranes of target cells. DMSO may also enhance tissueabsorption. More particularly, without being bound by the theory, it isbelieved that DMSO displaces water from the lipid head groups andprotein domains of the lipid bilayer of the cell membrane of targetcells, which indirectly loosens the lipid structure and acceleratesabsorption and penetration of the hydrophobic therapeutic agent.

Embodiments of the preparation of balloon catheters have been describedin detail. Further embodiments directed to uses of balloon catheterswill now be described.

III. Uses of Balloon Catheters

Uses of the balloon catheters as previously discussed are disclosed.Generally, the balloon catheter 10 is employed to deliver a hydrophobictherapeutic agent to a blood vessel while the balloon catheter 10 isdeployed at a target site of the blood vessel. More particularly, theballoon catheter 10 is employed to deliver an anti-proliferativehydrophobic therapeutic agent (such as paclitaxel or rapamycin) tovascular tissue through brief, direct pressure contact at high drugconcentration during balloon angioplasty. Such techniques may beemployed in treating a total occlusion or a narrowing of passages. Suchtechniques may also be employed to inhibit hyperplasia and restenosis,as the hydrophobic therapeutic agent may be retained in the targettissue at the delivery site.

The balloon catheter 10 may also be employed in combination with othermethods for treating the vasculature, such as with photodynamic therapyor atherectomy. With regard to photodynamic therapy, photodynamictherapy is a procedure where light or irradiated energy is used to killtarget cells in a patient. A light-activated photosensitizinghydrophobic therapeutic agent may be delivered to specific areas oftissue by the balloon catheter 10. A targeted light or radiation sourceselectively activates the hydrophobic therapeutic agent to produce acytotoxic response and mediate a therapeutic anti-proliferative effect.

With regard to atherectomy, atherectomy is a procedure employed toremove plaque from arteries. More specifically, atherectomy removesplaque from peripheral and coronary arteries. The medical device usedfor peripheral or coronary atherectomy may be a laser catheter, arotational atherectomy device such as a Rotablator® (Boston Scientific,Quincy, Mass.), or a direct atherectomy device on the end of a catheter.During atherectomy, a catheter is inserted into the body and advancedthrough an artery to the area of narrowing. After the atherectomy hasremoved some of the plaque, balloon angioplasty using the coated ballooncatheter 10 may be performed. In addition, stenting may also beperformed thereafter, or simultaneous with expansion of the coatedexpandable balloon 12 as described above.

EXAMPLES

The following examples include embodiments of balloon catheters andcoating layers within the scope of the present disclosure. While thefollowing examples are considered to embody the present disclosure, theexamples should not be interpreted as limitations upon the presentdisclosure.

Example 1 Preparation of Coating Solutions

Experimental Protocol. Coating solutions for balloon catheters wereprepared. More particularly, coating solutions for balloon cathetersincluding Formulations I-XI were prepared. Formulations I-XI are setforth in Table 1 below.

TABLE 1 HYDROPHOBIC FORMULATION THERAPEUTIC NO. AGENT ADDITIVE(S)SOLVENT I Paclitaxel Gluconolactone Acetone, Ethanol, Water IIPaclitaxel Tween 20, N-octanoyl Acetone, Ethanol N-methylglucamine IIIPaclitaxel Tween 20, Sorbitol Acetone, Ethanol, Water IV PaclitaxelMeglumine, Gensitic Acid Acetone, Ethanol V Paclitaxel Lactobionic Acid,Acetone, Ethanol, Diethanolamine Water VI Paclitaxel N-Octanoyl-N-Acetone, Ethanol methylglucamine VII Paclitaxel Meglumine, Lactic AcidAcetone, Ethanol, Water VIII Paclitaxel Gensitic Acid, Acetone, Ethanol,Diethanolamine Water IX Paclitaxel Triton X-100, N-heptanoyl Acetone,Ethanol N-Methylglucamine X Paclitaxel Ultravist 370 Ethanol, Acetone XIPaclitaxel N/A Ethanol, Acetone

Preparation of Coating Solution Formulations I-XI in Table I is setforth below.

Formulation I. 50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 0.4-1.0 ml water, and 50-200 mg gluconolactone weremixed.

Formulation II. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 35-70 mg Tween 20, and 35-70 mg N-octanoylN-methylglucamine were mixed.

Formulation III. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-1.0 mlacetone, 0.4-1.0 ml ethanol, 0.2-0.4 ml water, 35-70 mg Tween 20, and35-70 mg sorbitol were mixed.

Formulation IV. 40-80 mg (0.048-0.096 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 40-80 mg meglumine, and 32-64 mg gensiticacid (equal molar ratio with meglumine) were mixed.

Formulation V. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-0.8 mlacetone, 0.4-0.8 ml ethanol, 0.25-0.50 ml water, 35-70 mg lactobionicacid, and 10-20 mg diethanolamine (equal molar ratio with lactobionicacid) were mixed.

Formulation VI. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, and 70-140 mg N-octanoyl N-methylglucaminewere mixed.

Formulation VII. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-0.8 mlacetone, 0.4-0.8 ml ethanol, 0.2-0.4 ml water, 35-70 mg meglumine, and18-36 mg lactic acid (equal molar ratio with meglumine) were mixed.

Formulation VIII. 50-100 mg (0.06-0.12 mmole) paclitaxel, 0.8-1.6 mlacetone, 0.8-1.6 ml ethanol, 0.4-1.0 ml water, 50-100 mg gensitic acid,and 30-60 mg diethanolamine (equal molar ratio with gensitic acid) weremixed.

Formulation IX. 35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 35-70 mg Triton X-100, and 35-70 mgN-heptanoyl N-methylglucamine were mixed.

Formulation X—Comparison Solution 1. 50 mg (0.06 mmole) paclitaxel, 1 mlethanol, 0.2 ml acetone, 0.042 ml Ultravist 370 were mixed.

Formulation XI—Comparison Solution 2. 40 mg (0.048 mmole) paclitaxel,0.5 ml ethanol, 0.5 ml acetone were mixed.

Example 2 Coating of PTCA Balloon Catheters

Experimental Protocol. PTCA balloon catheters were coated with thecoating solutions including Formulations I-XI prepared in Example 1.More specifically, 6 PTCA balloon catheters (3.5 and 3.0 mm in diameterand 20 mm in length) were inflated at 1-3 atm. The inflated balloon wasloaded with one of the coating solutions including Formulations I-XIfrom Example 1. A sufficient amount of paclitaxel on the balloon (3microgram per square mm) was obtained. The inflated balloons werefolded, and then dried. The coated folded balloon was then rewrapped andsterilized for animal testing.

Example 3 Delivering Paclitaxel from the Coated PTCA Balloon Cathetersto Target Sites

Experimental Protocol. Paclitaxel was delivered to target sites in thecoronary vasculature of pigs from the coated PTCA balloon cathetersprepared in Example 2. More specifically, the coated PTCA ballooncatheters from Example 2 were inserted into a target site in thecoronary vasculature (LAD, LCX and RCA) of a 25-45 pound pig. Theballoons were inflated to about 12 atm. The overstretch ratio (the ratioof balloon diameter to vessel diameter) was about 1.15-1.20. Thepaclitaxel delivered into the target tissue during 30-60 seconds ofinflation. The balloon catheter was then deflated and withdrawn from theanimal body. The target blood vessel was harvested 0.25-24 hours afterthe procedure. The paclitaxel content in the target tissue and theresidual paclitaxel remaining on the balloon were analyzed by tissueextraction and HPLC.

In some of these animal studies, a stent was crimped on the coatedballoon catheters from Example 2 prior to deployment. In chronic animaltests, angiography was performed before and after all interventions andat 28-35 days after the procedure. Luminal diameters were measured andlate lumen loss was calculated. Late lumen loss is the differencebetween the minimal lumen diameter measured after a period of follow-uptime (usually weeks to months after an intervention, such as angioplastyand stent placement in the case of this example) and the minimal lumendiameter measured immediately after the intervention. Restenosis may bequantified by the diameter stenosis, which is the difference between themean lumen diameters at follow-up and immediately after the proceduredivided by the mean lumen diameter immediately after the procedure. Theanimal test results for the Formulations I-XI from Example 1 arereported below.

Experimental Results. All data is an average of five or six experimentaldata points.

Formulation I. The paclitaxel content of the Formulation I from Example1 on the 3.5 mm balloon catheters was 3.26 μg/mm². After the procedure,the paclitaxel on the balloon was 15.92 μg, or 2.3% of the totalpaclitaxel loaded on the balloon. The paclitaxel content in tissueharvested 15-30 minutes after the procedure was 64.79 μg, or 9.2% of thetotal paclitaxel content originally loaded on the balloon. When an 18 mmstent was deployed by the coated balloon, the residual paclitaxel on theballoon was 31.96 μg, or 4.5% of paclitaxel load, and the paclitaxelcontent in tissue harvested 15-30 minutes after the procedure was 96.49μg, or 13.7% of paclitaxel load. The stretch ratio is 1.3 in theprocedure. The late lumen loss after 28-35 days was 0.10 (sd 0.2) mm.The diameter stenosis is 3.3%.

Formulation II. The paclitaxel content of the Formulation II fromExample 1 on the 3.5 mm balloon catheters was 3.08 μg/mm². After theprocedure, the residual paclitaxel on the balloon was 80.58 μg, or 11.4%of the total paclitaxel load. The paclitaxel content in tissue harvested15-30 minutes after the procedure was 42.23 μg, or 6.0% of the totalpaclitaxel load. After 28-35 days late lumen loss was 0.30 (sd 0.23) mm.The diameter stenosis was 5.4%.

Formulation III. The paclitaxel content of the Formulation III fromExample 1 on the 3.5 mm balloon catheters was 3.61 μg/mm². After theprocedure, the residual paclitaxel on the balloon was 174.24 μg, or24.7% of the total paclitaxel load. The paclitaxel content in tissueharvested 15-30 minutes after the procedure was 83.83 μg, or 11.9% ofthe total drug load. When deployed with a pre-crimped 18 mm stent, theresidual paclitaxel on the balloon is 114.53 μg, or 16.1% of the totalpaclitaxel load, and the paclitaxel content in tissue harvested 15-30minutes post procedure was 147.95 μg, or 18.1% of the total paclitaxelload. The stretch ratio was 1.3 in the procedure. The late lumen lossafter 28-35 days was 0.10 (sd 0.1) mm. The diameter stenosis was 3.4%.

Formulation IV. The paclitaxel content of the Formulation IV fromExample 1 on the 3.5 mm balloon catheters was 4.71 μg/mm². After theprocedure, the residual paclitaxel on the balloon was 44.39 μg, or 6.3%of the total paclitaxel load. The paclitaxel content in the tissueharvested 15-30 minutes after the procedure was 77.87 μg, or 11.0% ofthe total paclitaxel load. After 28-35 days late lumen loss was 0.23 (sd0.44) mm. The diameter stenosis was 7.3%.

Formulation V. The paclitaxel content of the Formulation V from Example1 on the 3.5 mm balloon catheters was 3.85 μg/mm². After the procedure,residual paclitaxel on the balloon was 24.59 μg, or 3.5% of the totalpaclitaxel load. The paclitaxel content in tissue harvested 15-30minutes after the procedure was 37.97 μg, or 5.4% of the totalpaclitaxel load. After 28-35 days late lumen loss was 0.33 (sd 0.14) mm.The diameter stenosis was 6.7%.

Formulation VI. The paclitaxel content of the Formulation VI fromExample 1 on the 3.5 mm balloon catheters was 3.75 μg/mm². After theprocedure, residual paclitaxel on the balloon was 0.82 μg, or 0.1% ofthe total paclitaxel load. The paclitaxel content in tissue harvested 60minutes after the procedure was 45.23 μg, or 5.5% of the totalpaclitaxel load. After 28-35 days late lumen loss was 0.49 (sd 0.26) mm.The diameter stenosis was 11.3%.

Formulation VII. The paclitaxel content of the Formulation VII fromExample 1 on the 3.5 mm balloon catheters was 3.35 μg/mm². After theprocedure, the residual paclitaxel on the balloon was 62.07 μg, or 7.5%of the total paclitaxel load. The paclitaxel content in tissue harvested60 minutes after the procedure was 40.55 μg, or 4.9% of the totalpaclitaxel load. After 28-35 days late lumen loss was 0.47 (sd 0.33) mm.The diameter stenosis was 9.9%.

Formulation VIII. The paclitaxel content of the Formulation VIII fromExample 1 on the 3.5 mm balloon catheters was 3.41 μg/mm². After theprocedure, residual paclitaxel on the balloon was 50.0 μg, or 6.0% ofthe total paclitaxel load. The paclitaxel content in tissue harvested 60minutes post procedure was 26.72 μg, or 3.2% of the total paclitaxelload. After 28-35 days late lumen loss was 0.36 (sd 0.41) mm. Thediameter stenosis was 9.3%.

Formulation IX. The paclitaxel content of the Formulation IX fromExample 1 on the 3.5 mm balloon catheters was 3.10 μg/mm². After theprocedure, residual paclitaxel on the balloon was 1.9% of the totalpaclitaxel load. The paclitaxel content in tissue harvested 2 hoursafter the procedure was 34.17 μg, or 5.0% of the total paclitaxel load.In tissue harvested 24 hours after the procedure, the paclitaxel contentin tissue was 28.92 μg, or 4.2% of the total paclitaxel load.

Control Formulation. The drug content of control formulation (uncoatedballoon) on the 3.5 mm balloon catheters was 0.0 μg/mm². After theprocedure, residual drug on the balloon was 0% of the total drug load.The drug content in tissue harvested 15 minutes after the procedure was0 μg. In tissue harvested 24 hours after the procedure, the drug contentin tissue was 0 μg. After 28-35 days late lumen loss was 0.67 (sd 0.27)mm. The diameter stenosis is 20.8%. In the second repeat experiment, thestretch ratio was 1.3. The late lumen loss was 1.1 (sd 0.1). Thediameter stenosis was 37.5%.

Formulation X—Comparison Solution 1. The paclitaxel content of theFormulation X from Example 1 on the 3.5 mm balloon catheters was 3.21μg/mm². After the procedure, residual paclitaxel on the balloon was13.52 μg, or 1.9% of the total paclitaxel load. The paclitaxel contentin the tissue was 28.32 μg, or 4.0% of the total paclitaxel load. Whenthe balloon was deployed with a pre-crimped 18 mm stent, residualpaclitaxel on the balloon was 26.45 μg, or 3.7% of the total paclitaxelload. The paclitaxel content in tissue was 113.79 μg, or 16.1% of drugload. After 28-35 days, late lumen loss was 0.27 (sd 0.15) mm. Thediameter stenosis was 7.1%.

Formulation XI—Comparison Solution 2. The paclitaxel content of theFormulation XI (without additive) on the 3.5 mm balloon catheters was4.22 μg/mm². After the procedure, residual paclitaxel on the balloon was321.97 μg, or 45.6% of the total paclitaxel load. The paclitaxel contentin the tissue was 12.83 μg, or 1.8% of the total paclitaxel load.

Surprisingly, the concentration of paclitaxel absorbed by porcinecoronary artery tissue after deployment of balloons coated with theFormulations I-IX from Example 1 according to embodiments of the presentdisclosure was higher than that delivered by balloons coated with theFormulation X from Example 1 and higher than those coated withpaclitaxel alone, the Formulation XI from Example 1. The late lumen lossafter 28-35 days follow up was less than the control (uncoated balloon).

What is claimed is:
 1. A balloon catheter for delivering a therapeuticagent to target site in a blood vessel, the balloon catheter comprising:a coating layer overlying an exterior surface of a balloon, the coatinglayer comprising a therapeutic agent and at least one first additive,wherein: the therapeutic agent is selected from the group consisting ofpaclitaxel, rapamycin, beta-lapachone, biologically active vitamin D,and combinations thereof; and the at least one first additive comprisesa PEG fatty ester selected from the group consisting of PEG laurates,PEG oleates, PEG stearates, PEG glyceryl laurates, PEG glyceryl oleates,PEG glyceryl stearates, PEG sorbitan monolaurates, PEG sorbitanmonooleates, PEG sorbitan stearates, PEG sorbitan laurates, PEG sorbitanoleates, PEG sorbitan palmitates, and combinations thereof; and abiocompatible polymer.
 2. The balloon catheter of claim 1, wherein thebiocompatible polymer is present in an adherent layer.
 3. The ballooncatheter of claim 2, wherein the adherent layer is positioned betweenthe coating layer and the exterior surface of the balloon.
 4. Theballoon catheter of claim 1, wherein the biocompatible polymer isselected from the group consisting of polyolefins, polyisobutylene,ethylene-1-olefin copolymers, acrylic polymers, polyvinyl chloride,polyvinyl methyl ether, polyvinylidene fluoride, polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinylacetate, ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, Nylon 12, polycaprolactone, epoxy resins,polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulosebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, chitins, polylactic acid, polyglycolicacid, polylactic acidpolyethylene oxide copolymers, silicones, ethylenevinyl acetate copolymers, EPDM rubbers, and mixtures and blockcopolymers thereof.
 5. The balloon catheter of claim 2, wherein theadherent layer does not contain a therapeutic agent.
 6. The ballooncatheter of claim 1, wherein the at least one first additive is selectedfrom the group consisting of PEG-20 sorbitan monolaurate, PEG-20sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitanmonooleate, and combinations thereof.
 7. The balloon catheter of claim1, wherein the at least one first additive is selected from the groupconsisting of PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate,and combinations thereof.
 8. The balloon catheter of claim 1, whereinthe coating layer further comprises a second additive selected from thegroup consisting of polyglyceryl-10 oleate, octoxynol-9,p-isononylphenoxypolyglycidol, Tyloxapol, niacinamide, nicotinic acid,thiamine hydrochloride, 2-pyrrolidone-5-carboxylic acid, gluconolactone,sorbitol, meglumine, lactobionic acid, N-octanoyl-N-methylglucamine,lactic acid, gensitic acid, diethanolamine, and combinations thereof. 9.The balloon catheter of claim 8, wherein the second additive is selectedfrom the group consisting of polyglyceryl-10 oleate,p-isononylphenoxypolyglycidol, gluconolactone, sorbitol, lactobionicacid, N-octanoyl-N-methylglucamine, and combinations thereof.
 10. Theballoon catheter of claim 8, wherein the second additive is selectedfrom the group consisting of gluconolactone, sorbitol, lactobionic acid,N-octanoyl-N-methylglucamine, and combinations thereof.
 11. The ballooncatheter of claim 8, wherein the second additive is selected from thegroup consisting of gluconolactone, sorbitol, and combinations thereof.12. The balloon catheter of claim 8, wherein the at least one firstadditive is PEG-20 sorbitan monolaurate and the second additive isselected from the group consisting of gluconolactone, sorbitol,lactobionic acid, N-octanoyl-N-methylglucamine, and combinationsthereof.
 13. The balloon catheter of claim 8, wherein the at least onefirst additive is PEG-20 sorbitan monolaurate, and the second additiveis selected from the group consisting of gluconolactone, sorbitol andcombinations thereof.
 14. The balloon catheter of claim 8, wherein thetherapeutic agent is paclitaxel, the at least one first additive isPEG-20 sorbitan monolaurate, and the second additive is selected fromthe group consisting of gluconolactone, sorbitol, and combinationsthereof.
 15. The balloon catheter of claim 8, wherein the therapeuticagent is paclitaxel, the at least one first additive is PEG-20 sorbitanmonolaurate, and the second additive is gluconolactone.
 16. The ballooncatheter of claim 8, wherein the therapeutic agent is paclitaxel, the atleast one first additive is PEG-20 sorbitan monolaurate, and the secondadditive is sorbitol.
 17. The balloon catheter of claim 1, wherein thecoating layer further comprises an antioxidant.
 18. The balloon catheterof claim 1, wherein the concentration of the therapeutic agent in thecoating layer is from 1 to 20 ug/mm².
 19. The balloon catheter of claim1, wherein the ratio by weight of the at least one first additive to thetherapeutic agent in the coating layer is from about 0.1 to
 5. 20. Theballoon catheter of claim 1, wherein the at least one first additive isnot a therapeutic agent.